This invention relates to compositions and methods for delivery of biocompatible particles to a selected location in a body, and, more particularly, relates to particles capable of carrying biologically active compounds, which provide for targeted magnetic transport of the particles and the maintenance of them in a predetermined place for localized diagnostic or therapeutic treatment of disease.
Metallic carrier compositions used in the treatment of various disorders have been heretofore suggested and/or utilized (see, for example, U.S. Pat. Nos. 4,849,209 and 4,106,488), and have included such compositions that are guided or controlled in a body in response to external application of a magnetic field (see, for example, U.S. Pat. Nos. 4,501,726, 4,652,257 and 4,690,130). Such compositions have not always proven practical and/or entirely effective. For example, such compositions may lack adequate capacity for carriage of the desired biologically active agent to the treatment site, have less than desirable magnetic susceptibility and/or be difficult to manufacture, store and/or use.
One such known composition, deliverable by way of intravascular injection, includes microspheres made up of a ferromagnetic component covered with a biocompatible polymer (albumin, gelatin, and polysaccharides) which also contains a drug (Driscol C. F. et al. Prog. Am. Assoc. Cancer Res., 1980, p. 261).
It is possible to produce albumen microspheres up to 3.0 xcexcm in size containing a magnetic material (magnetite Fe3O4) and the anti-tumoral antibiotic doxorubicin (Widder K. et al. J. Pharm. Sci., 68:79-82 1979). Such microspheres are produced through thermal and/or chemical denaturation of albumin in an emulsion (water in oil), with the input phase containing a magnetite suspension in a medicinal solution. Similar technique has been used to produce magnetically controlled, or guided, microcapsules covered with ethylcellulose containing the antibiotic mitomycin-C (Fujimoto S. et al., Cancer, 56: 2404-2410,1985).
Another method is to produce magnetically controlled liposomes 200 nm to 800 nm in size carrying preparations that can dissolve atherosclerotic formations. This method is based on the ability of phospholipids to create closed membrane structures in the presence of water (Gregoriadis G., Ryman B. E., Biochem. J., 124:58, 1971).
The above compositions require extremely high flux density magnetic fields for their control, and are somewhat difficult to produce consistently, sterilize, and store on an industrial scale without changing their designated properties.
To overcome these shortcomings, a method for producing magnetically controlled dispersion has been suggested (See European Patent Office Publication No. 0 451 299 A1, by Kholodov L. E., Volkonsky V. A., Kolesnik N. F. et al.), using ferrocarbon particles as a ferromagnetic material. The ferrocarbon particles are produced by heating iron powder made up of particles 100 xcexcm to 500 xcexcm in size at temperatures of 800xc2x0 C. to 1200xc2x0 C. in an oxygen-containing atmosphere. The mixture is subsequently treated by carbon monoxide at 400xc2x0 C. to 700xc2x0 C. until carbon particles in an amount of about 10% to 90% by mass begin emerging on the surface. A biologically active substance is then adsorbed on the particles
This method of manufacturing ferrocarbon particles is rather complicated and requires a considerable amount of energy. Because the ferromagnetic component is oxidized due to the synthesis of ferrocarbon particles at a high temperature in an oxygen containing atmosphere, magnetic susceptibility of the dispersion obtained is decreased by about one-half on the average, as compared with metallic iron. The typical upper limit of adsorption of a biologically active substance on such particles is about 2.0% to 2.5% of the mass of a ferromagnetic particle.
The magnetically controlled particle produced by the above method has a spherical ferromagnetic component with a thread-like carbon chain extending from it and is generally about 2.0 xcexcm in size. The structure is believed to predetermine the relatively low adsorption capacity of the composites and also leads to breaking of the fragile thread-like chains of carbon from the ferromagnetic component during storage and transportation.
Thus, there remains a need for an effective biocompatible composition which is capable of being transported magnetically, and which is relatively easy to manufacture, store and use.
This invention provides a magnetically responsive composition which may carry biologically active substances, or which may be used alone. Generally, any soluted substance can be carried, many of which have been heretofore suggested. For example, without limitation, alkylating agents, antimetabolites, antifungals, anti-inflammatory, antitumor, and chemotherapy agents, and suitable combinations thereof can be adsorbed on the particles. Other therapeutic agents and drugs, such as systemic toxicity inhibitors, antibiotics and hydrocortisone, or the like, can also be carried and administered in vivo by use of the magnetically controlled carrier particles of the invention. Methods of production and use thereof are also provided.
The aim of this invention is to improve some parameters of magnetically controlled compositions used for the targeted transport of biocompatible particles, including increasing relative adsorption capacity, increasing magnetic susceptibility, intensifying diagnostic and therapeutic effect and ease of use, as well as simplifying the technology of manufacturing the magnetically controlled composition and ensuring its guaranteed long storage without changing its desired characteristics.
This is achieved by using suitable composite,volume compounded ferrocarbon particles as a magnetically susceptible material for a magnetically controlled composition. These particles have a major dimension (i.e., largest diameter) of about 0.2 xcexcm to about 5.0 xcexcm (and preferably from 0.5 xcexcm to 5.0 xcexcm) and contain from about 1.0% to about 95.0% (by mass) of carbon, with the carbon strongly connected to iron. The particles-are obtained by jointly deforming (i.e., milling) a mixture of iron and carbon powders. In some cases the finished particles include trace amounts of the compound cementite (Fe3C).
The composition utilized for localized in vivo treatment of disease includes particles of about 0.5 xcexcm and 5 xcexcm in major dimension, each particle including carbon and iron and, optionally, a biologically active substance selected for its efficacy in diagnosing or treating the disease adsorbed on the particles.
The method of producing the composition includes the step of jointly deforming a mechanical mixture of iron and carbon powders for a time sufficient to bind the powders into a composite of iron:carbon particles having an average major dimension of less than 5 xcexcm in size, and with a substantial portion of the particles including about 1.0% to 95.0% by mass of carbon distributed throughout the volume of each of the particles. The particles are preferably separated to select particles having a major dimension of from about 0.5 xcexcm to about 5.0 xcexcm, after which up to 20% by mass of the particles of a biologically active substance can be adsorbed onto the selected particles.
The methods of use include methods for localized in vivo diagnosis or treatment of disease comprising providing a magnetically responsive ferrocarbon carrier (such as the carrier of this invention) having adsorbed thereon a biologically active substance selected for its efficacy in diagnosing or treating the disease, and injecting the carrier into the body of a patient. For example, the carrier is injected by inserting delivery means into an artery to within a short distance from a body site to be treated and at a branch or branches (preferably the most immediate) to a network of arteries carrying blood to the site. The carrier is injected through the delivery means into the blood vessel. Just prior to injection, a magnetic field is established exterior to the body and adjacent to the site of sufficient field strength to guide a substantial quantity of the injected carrier to, and retain the substantial quantity of the carrier at, the site. Preferably, the magnetic field is of sufficient strength to draw the carrier into the soft tissue at the site adjacent to the network of vessels, thus avoiding substantial embolization of any of the larger vessels by the carrier particles.
It is therefore an object of this invention to provide an improved magnetically responsive composition for optionally carrying biologically active substances and methods of production and use thereof.
It is another object of this invention to provide a magnetically responsive carrier for biologically active substances which has improved magnetic responsiveness, yet is durable during storage and use, and includes up to about 20% by mass of a biologically active substance adsorbed thereon.
It is another object of this invention to provide a magnetically responsive composition comprising particles having a major dimension of from about 0.5 xcexcm to about 5.0 xcexcm, each iron:carbon composite particle including about 1.0% to about 95.0% by mass of carbon distributed throughout the volume of the particle.
It is still another object of this invention to provide a composition utilized for localized in vivo diagnosis or treatment of disease including a carrier with composite iron:carbon particles from about 0.5 xcexcm to about 5.0 xcexcm in size, each composite iron:carbon particle including carbon and iron with the carbon distributed throughout the volume of the particle, and an optional biologically active substance selected for its efficacy in diagnosing or treating the disease which is adsorbed on the particles.
It is yet another object of this invention to provide a method of producing a magnetically responsive carrier composition including composite iron:carbon particles including carbon and iron with the carbon distributed throughout the volume of each of the particles.
It is yet another object of this invention to provide liquid and dry kits for administering a composition utilized for localized in vivo diagnosis or treatment of disease including a ferrocarbon particle with an optional biologically active substance adsorbed thereon that has been selected for its efficacy in diagnosing or treating the disease.
It is a further object of this invention to provide methods of sterilization of the components of the kits supplied for administering a composition utilized for localized in vivo diagnosis or treatment of disease including a ferrocarbon particle with an optional biologically active substance adsorbed thereon that has been selected for its efficacy in diagnosing or treating the disease.
With these and other objects in view, which will become apparent to one skilled in the art from the following description, this invention resides in the novel construction, combination, arrangement of parts and methods substantially as hereinafter described, and more particularly defined by the appended claims, it being understood that changes in the precise embodiment of the herein disclosed invention are meant to be included as they come within the scope of the claims.